IgG Testing, Immunoglobulin Replacement Therapy, and Infection Outcomes in Patients with CLL or NHL: Real-World Evidence.

Patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) can develop hypogammaglobulinemia, a form of secondary immune deficiency (SID), from the disease and treatments. Patients with hypogammaglobulinemia with recurrent infections may benefit from immunoglobulin replacement therapy (IgRT). This study evaluated patterns of IgG testing and the effectiveness of IgRT in real-world patients with CLL or NHL. A retrospective, longitudinal study was conducted among adult patients diagnosed with CLL or NHL. Clinical data from the Massachusetts General Brigham Research Patient Data Registry were used. IgG testing, infections, and antimicrobial use were compared before vs. 3, 6, and 12 months after IgRT initiation. Generalized estimating equation logistic regression models were used to estimate odds ratios (OR), 95% Confidence Intervals (CIs), and P-values. The study population included 17,192 patients (CLL: N=3,960; median age, 68 years; NHL: N=13,232; median age, 64 years). In the CLL and NHL cohorts, 67% and 51.2% had IgG testing and 6.5% and 4.7% received IgRT, respectively. Following IgRT initiation, the proportion of patients with hypogammaglobulinemia, the odds of infections or severe infections, and associated antimicrobial use, decreased significantly. Increased frequency of IgG testing was associated with a significantly lower likelihood of severe infection. In conclusion, in real-world patients with CLL or NHL, IgRT was associated with significant reductions in hypogammaglobulinemia, infections, severe infections, and associated antimicrobials. Optimizing IgG testing and IgRT are warranted for the comprehensive management of SID in patients with CLL or NHL.

Context matters: Tumor microenvironments impact cellular therapy success.

In a recent publication, Locke et al. present data from pretreatment tumor biopsies taken on the ZUMA-7 trial. Their results identify tumor microenvironment (TME) contexts and level of CD19 expression as prognostic indicators for responses to axicabtagene ciloleucel (axi-cel).

Effect of an initial specimen diversion device on blood-culture contamination rates and vancomycin usage: A quasi-experimental study.

Initial specimen diversion devices (ISDDs) are a potential solution for reducing blood-culture contamination rates. We report the implementation of an ISDD associated with a sustained reduction in blood-culture contamination rates for >18 months after implementation. We did not observe a clinically significant reduction in inpatient vancomycin usage.

Diagnostic stewardship for human immunodeficiency virus (HIV) testing using computerized physician order entry.

Altering the appearance of a computerized physician order entry (CPOE) interface reduces misuse of an HIV diagnostic test by 87%, demonstrating that CPOE design is a key component of diagnostic stewardship. Collaboration between infectious disease providers, clinical laboratorians, and information technology (IT) professionals can result in improved quality and decreased costs.

IRF4 expression by lung dendritic cells drives acute but not Trm cell-dependent memory Th2 responses.

Expression of the transcription factor interferon regulatory factor 4 (IRF4) is required for the development of lung conventional DCs type 2 (cDC2s) that elicit Th2 responses, yet how IRF4 functions in lung cDC2s throughout the acute and memory allergic response is not clear. Here, we used a mouse model that loses IRF4 expression after lung cDC2 development to demonstrate that mice with IRF4-deficient DCs display impaired memory responses to allergen. This defect in the memory response was a direct result of ineffective Th2 induction and impaired recruitment of activated effector T cells to the lung after sensitization. IRF4-deficient DCs demonstrated defects in their migration to the draining lymph node and in T cell priming. Finally, T cells primed by IRF4-competent DCs mediated potent memory responses independently of IRF4-expressing DCs, demonstrating that IRF4-expressing DCs are not necessary during the memory response. Thus, IRF4 controlled a program in mature DCs governing Th2 priming and effector responses, but IRF4-expressing DCs were dispensable during tissue-resident memory T cell-dependent memory responses.

Challenges of integrating economics into epidemiological analysis of and policy responses to emerging infectious diseases.

COVID-19 has shown that the consequences of a pandemic are wider-reaching than cases and deaths. Morbidity and mortality are important direct costs, but infectious diseases generate other direct and indirect benefits and costs as the economy responds to these shocks: some people lose, others gain and people modify their behaviours in ways that redistribute these benefits and costs. These additional effects feedback on health outcomes to create a complicated interdependent system of health and non-health outcomes. As a result, interventions primarily intended to reduce the burden of disease can have wider societal and economic effects and more complicated and unintended, but possibly not anticipable, system-level influences on the epidemiological dynamics themselves. Capturing these effects requires a systems approach that encompasses more direct health outcomes. Towards this end, in this article we discuss the importance of integrating epidemiology and economic models, setting out the key challenges which such a merging of epidemiology and economics presents. We conclude that understanding people's behaviour in the context of interventions is key to developing a more complete and integrated economic-epidemiological approach; and a wider perspective on the benefits and costs of interventions (and who these fall upon) will help society better understand how to respond to future pandemics.

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy.

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is because of a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation, and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.SIGNIFICANCE STATEMENT People with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathologic bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE, and supports a long-standing hypothesis of episodic memory theories.

Understanding the Barriers to Pooled SARS-CoV-2 Testing in the United States.

Pooled testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is instrumental for increasing test capacity while decreasing test cost. Pooled testing programs permit sustainable, long-term surveillance measures, which are essential for the early detection of virus resurgence in communities or the emergence of variants of concern. While numerous pooled approaches have been proposed to increase test capacity, uptake by laboratories has been limited. On 9 December 2020, we invited 362 U.S. laboratories that inquired about the Yale School of Public Health SalivaDirect test to participate in a survey to evaluate testing constraints and pooling strategies for SARS-CoV-2 testing. The survey was distributed using Qualtrics, and three reminders were sent. The survey closed on 21 January 2021. Of 93 responses received (25.7% response rate), 90 were from Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories conducting SARS-CoV-2 testing. The remaining three were excluded from the analyses. Responses indicated that the major barriers to the uptake of pooled testing in the United States may not simply be the number of tests a laboratory can process per day, but rather the lack of clear protocols and adequate resources; laboratories are working with fixed physical and human capital constraints. Importantly, laboratories across the country are heterogeneous in infrastructure and workflow. The need for SARS-CoV-2 testing will remain for years to come. Testing programs can be maintained through pooled PCR testing strategies, and while statisticians, operations researchers, and others with expertise in sampling design have important value to add, laboratories require support on how to transition from traditional diagnostic testing to pooled surveillance. IMPORTANCE While numerous pooled SARS-CoV-2 testing approaches have been described in an effort to increase testing capacity and decrease test prices, uptake by laboratories has been limited. Responses to our survey of United States-based laboratories highlight the importance of consulting end-users-those that solutions are being designed for-so challenges can be addressed in a manner tailored to meet the specific needs out in the field. It may be surprising to those designing pooled testing strategies to learn that laboratories view pooling as more time-consuming than testing samples individually, and therefore that it is thought to create delays in test reporting.

Maximizing the Efficiency of Active Case Finding for SARS-CoV-2 Using Bandit Algorithms.

Even as vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expands in the United States, cases will linger among unvaccinated individuals for at least the next year, allowing the spread of the coronavirus to continue in communities across the country. Detecting these infections, particularly asymptomatic ones, is critical to stemming further transmission of the virus in the months ahead. This will require active surveillance efforts in which these undetected cases are proactively sought out rather than waiting for individuals to present to testing sites for diagnosis. However, finding these pockets of asymptomatic cases (i.e., hotspots) is akin to searching for needles in a haystack as choosing where and when to test within communities is hampered by a lack of epidemiological information to guide decision makers' allocation of these resources. Making sequential decisions with partial information is a classic problem in decision science, the explore v. exploit dilemma. Using methods-bandit algorithms-similar to those used to search for other kinds of lost or hidden objects, from downed aircraft or underground oil deposits, we can address the explore v. exploit tradeoff facing active surveillance efforts and optimize the deployment of mobile testing resources to maximize the yield of new SARS-CoV-2 diagnoses. These bandit algorithms can be implemented easily as a guide to active case finding for SARS-CoV-2. A simple Thompson sampling algorithm and an extension of it to integrate spatial correlation in the data are now embedded in a fully functional prototype of a web app to allow policymakers to use either of these algorithms to target SARS-CoV-2 testing. In this instance, potential testing locations were identified by using mobility data from UberMedia to target high-frequency venues in Columbus, Ohio, as part of a planned feasibility study of the algorithms in the field. However, it is easily adaptable to other jurisdictions, requiring only a set of candidate test locations with point-to-point distances between all locations, whether or not mobility data are integrated into decision making in choosing places to test.

Measuring voluntary and policy-induced social distancing behavior during the COVID-19 pandemic.

Staying home and avoiding unnecessary contact is an important part of the effort to contain COVID-19 and limit deaths. Every state in the United States enacted policies to encourage distancing and some mandated staying home. Understanding how these policies interact with individuals' voluntary responses to the COVID-19 epidemic is a critical initial step in understanding the role of these nonpharmaceutical interventions in transmission dynamics and assessing policy impacts. We use variation in policy responses along with smart device data that measures the amount of time Americans stayed home to disentangle the extent that observed shifts in staying home behavior are induced by policy. We find evidence that stay-at-home orders and voluntary response to locally reported COVID-19 cases and deaths led to behavioral change. For the median county, which implemented a stay-at-home order with about two cases, we find that the response to stay-at-home orders increased time at home as if the county had experienced 29 additional local cases. However, the relative effect of stay-at-home orders was much greater in select counties. On the one hand, the mandate can be viewed as displacing a voluntary response to this rise in cases. On the other hand, policy accelerated the response, which likely helped reduce spread in the early phase of the pandemic. It is important to be able to attribute the relative role of self-interested behavior or policy mandates to understand the limits and opportunities for relying on voluntary behavior as opposed to imposing stay-at-home orders.

Understanding the barriers to pooled SARS-CoV-2 testing in the United States

Pooled testing for SARS-CoV-2 detection is instrumental for increasing test capacity while decreasing test cost, key factors for sustainable, long-term surveillance measures. While numerous pooled approaches have been described, uptake by labs has been limited. We surveyed 90 US labs to understand the barriers to implementing pooled testing.

Increased SARS-CoV-2 Testing Capacity with Pooled Saliva Samples.

We analyzed feasibility of pooling saliva samples for severe acute respiratory syndrome coronavirus 2 testing and found that sensitivity decreased according to pool size: 5 samples/pool, 7.4% reduction; 10 samples/pool, 11.1%; and 20 samples/pool, 14.8%. When virus prevalence is >2.6%, pools of 5 require fewer tests; when <0.6%, pools of 20 support screening strategies.

Sleep-wake characteristics in a mouse model of severe traumatic brain injury: Relation to posttraumatic epilepsy.

Study objectives: Traumatic brain injury (TBI) results in sequelae that include posttraumatic epilepsy (PTE) and sleep-wake disturbances. Here, we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI. Methods: Following controlled cortical impact (CCI) or sham injury (craniotomy only), CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2, or 3) 1-week-long video-EEG recordings were performed after the injury to examine epileptiform activity. High-amplitude interictal events were extracted from EEG using an automated method. After scoring sleep-wake patterns, sleep spindles and EEG delta power were derived from nonrapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed in sham and CCI cohorts to quantify the brain lesions. We then employed a no craniotomy (NC) control to perform 1-week-long EEG recordings at week 1 and month 1 after surgery. Results: Posttraumatic seizures were seen in the CCI group only, whereas interictal epileptiform activity was seen in CCI or sham. Sleep-wake disruptions consisted of shorter wake or NREM bout lengths and shorter duration or lower power for spindles in CCI and sham. NREM EEG delta power increased in CCI and sham groups compared with NC though the CCI group with posttraumatic seizures had lower power at a chronic time point compared with those without. Follow-up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes. Significance: In our TBI model, tracking changes in NREM delta power distinguishes between CCI acutely and animals that will eventually develop PTE, but further work is necessary to identify sleep biomarkers of PTE. Employing NC controls together with sham controls should be considered in future TBI studies.

Risk compensation and face mask mandates during the COVID-19 pandemic.

Face masks are an important component in controlling COVID-19, and policy orders to wear masks are common. However, behavioral responses are seldom additive, and exchanging one protective behavior for another could undermine the COVID-19 policy response. We use SafeGraph smart device location data and variation in the date that US states and counties issued face mask mandates as a set of natural experiments to investigate risk compensation behavior. We compare time at home and the number of visits to public locations before and after face mask orders conditional on multiple statistical controls. We find that face mask orders lead to risk compensation behavior. Americans subject to the mask orders spend 11-24 fewer minutes at home on average and increase visits to some commercial locations-most notably restaurants, which are a high-risk location. It is unclear if this would lead to a net increase or decrease in transmission. However, it is clear that mask orders would be an important part of an economic recovery if people otherwise overestimate the risk of visiting public places.

Preoperative cholangitis is an independent risk factor for mortality in patients after pancreatoduodenectomy for pancreatic cancer.

OBJECTIVES: Preoperative biliary stenting is required for patients with obstructive jaundice from pancreatic adenocarcinoma who are receiving neoadjuvant chemotherapy. While in most patients this approach results in durable biliary drainage, some patients develop cholangitis during neoadjuvant treatment. Further, several studies have shown that preoperative cholangitis in patients with hepatobiliary malignancies can result in substantially unfavorable outcomes. The aim of this study was to evaluate the impact of preoperative cholangitis in patients who underwent pancreaticoduodenectomy after completing neoadjuvant chemotherapy. METHODS: Participants: all adult patients (n = 449) diagnosed with pancreatic adenocarcinoma from January 1st, 2013 to March 31st, 2018 who pursued treatment at the Massachusetts General Hospital were screened. Of these 449 patients, 97 met final inclusion criteria of receiving neoadjuvant chemotherapy with intent to pursue curative surgery. Data were collected via retrospective chart review including baseline characteristics, survival, episodes of preoperative cholangitis, and surgical complications. RESULTS: In patients completing successful pancreaticoduodenectomy surgery, preoperative cholangitis is associated with increased mortality (HR 2.67, 95% CI:1.16-6.13). This finding is independent of postoperative outcomes or tumor recurrence rate. The presence of cholangitis did not impact completion of neoadjuvant chemotherapy (92% vs 85%, p = 0.5) or ability to proceed to surgery (76% vs 75%, p = 1.0). Preoperative cholangitis was not associated with postoperative morbidity (42.1% vs 45.1%, p = 1.0). CONCLUSIONS: One episode of cholangitis during neoadjuvant chemotherapy is associated with increased mortality following successful pancreaticoduodenectomy, independent of immediate postoperative outcomes or tumor recurrence. Preoperative cholangitis does not affect ability to pursue neoadjuvant chemotherapy or complete successful surgery. Patients who develop cholangitis during the neoadjuvant chemotherapy treatment phase may reflect a distinct phenotype of patients with PDAC with a complex and more challenging clinical course.

Pooling saliva to increase SARS-CoV-2 testing capacity.

Expanding testing capabilities is integral to managing the further spread of SARS-CoV-2 and developing reopening strategies, particularly in regards to identifying and isolating asymptomatic and pre-symptomatic individuals. Central to meeting testing demands are specimens that can be easily and reliably collected and laboratory capacity to rapidly ramp up to scale. We and others have demonstrated that high and consistent levels of SARS-CoV-2 RNA can be detected in saliva from COVID-19 inpatients, outpatients, and asymptomatic individuals. As saliva collection is non-invasive, extending this strategy to test pooled saliva samples from multiple individuals could thus provide a simple method to expand testing capacity. However, hesitation towards pooled sample testing arises due to the dilution of positive samples, potentially shifting weakly positive samples below the detection limit for SARS-CoV-2 and thereby decreasing the sensitivity. Here, we investigated the potential of pooling saliva samples by 5, 10, and 20 samples prior to RNA extraction and RT-qPCR detection of SARS-CoV-2. Based on samples tested, we conservatively estimated a reduction of 7.41%, 11.11%, and 14.81% sensitivity, for each of the pool sizes, respectively. Using these estimates we modeled anticipated changes in RT-qPCR cycle threshold to show the practical impact of pooling on results of SARS-CoV-2 testing. In tested populations with greater than 3% prevalence, testing samples in pools of 5 requires the least overall number of tests. Below 1% however, pools of 10 or 20 are more beneficial and likely more supportive of ongoing surveillance strategies.

Pooling saliva to increase SARS-CoV-2 testing capacity

Expanding testing capabilities is integral to managing the further spread of SARS-CoV-2 and developing reopening strategies, particularly in regards to identifying and isolating asymptomatic and pre-symptomatic individuals. Central to meeting testing demands are specimens that can be easily and reliably collected and laboratory capacity to rapidly ramp up to scale. We and others have demonstrated that high and consistent levels of SARS-CoV-2 RNA can be detected in saliva from COVID-19 inpatients, outpatients, and asymptomatic individuals. As saliva collection is non-invasive, extending this strategy to test pooled saliva samples from multiple individuals could thus provide a simple method to expand testing capacity. However, hesitation towards pooled sample testing arises due to the dilution of positive samples, potentially shifting weakly positive samples below the detection limit for SARS-CoV-2 and thereby decreasing the sensitivity. Here, we investigated the potential of pooling saliva samples by 5, 10, and 20 samples prior to RNA extraction and RT-qPCR detection of SARS-CoV-2. Based on samples tested, we conservatively estimated a reduction of 7.41%, 11.11%, and 14.81% sensitivity, for each of the pool sizes, respectively. Using these estimates we modeled anticipated changes in RT-qPCR cycle threshold to show the practical impact of pooling on results of SARS-CoV-2 testing. In tested populations with greater than 3% prevalence, testing samples in pools of 5 requires the least overall number of tests. Below 1% however, pools of 10 or 20 are more beneficial and likely more supportive of ongoing surveillance strategies.